Clopidogrel, methyl (+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, is an anticoagulant drug that inhibits platelet aggregation by selective binding to adenylate cyclase-coupled ADP receptors on the platelet surface. It is widely used for the prevention of atherothrombotic events such as myocardial infarction, stroke, peripheral arterial disease, acute coronary syndrome, and cardio-vascular death. The structure of the S-enantiomer of clopidogrel is shown below in structure (I):

Clopidogrel (Such as Plavix® and other generics) is currently only available as a tablet form containing 75 mg equivalents of the clopidogrel base; the drug is present in the bisulfate salt form. There is no liquid injectable or liquid oral dosage form currently available in the market. PLAVIX® is an antiplatelet medication approved by the U.S. Food and Drug Administration to reduce thrombotic events and patients with acute coronary syndrome. For an average loading dose (300 mg clopidogrel in a PLA VIX® tablet), the typical time to reach the desired therapeutic effect (e.g. platelet aggregation inhibition) varies from two to five hours probably due to delay in absorption, delay in system availability, or suboptimal bioavailability. If there is an immediate need for the procedure (such as percutaneous coronary intervention (PCI) in less than two to three hours), a larger than average dose of clopidogrel is usually administered to patient in order to achieve faster onset, which could potential cause deadly side effects such as hemorrhage, and long bleeding.
Therefore, there is an urgent need for liquid clopidogrel dosage form that could be administered as injectable or oral solution to achieve rapid therapeutic effect without increasing the dose. The ability to formulate clopidogrel in a biocompatible vehicle having minimum side effects and appropriate pharmadynamic profiles is critical to the use of clopidogrel as an intravenous or oral liquid agent. This is particular challenge for clopidogrel because of its lipophilicity, pH-dependent solubility with very low solubility at physiological pH, and extremely chemical instability at alkaline pH.
Clopidogrel is a weakly base with pKa of 4.5. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°. Clopidogrel free base is a semi-solid, oily form with high-viscosity, which causes problems in storage or handling process. Moreover, it has been reported that clopidogrel free base was not suitable for use in pharmaceutical dosage forms, which is unstable under increased moisture and temperature. Due to a labile proton in the chiral center and the methyl ester group, it was very susceptible to racemization, oxidation, and hydrolysis of a methyl ester group. It was reported that antioxidants did not prevent this degradation, and higher pH accelerated instability. As a result, it was indicated that clopidogrel should only be stabilized with salt-forming acids before incorporated into dosage forms.
Clopidogrel bisulfate, which is currently used in the commercial oral tablet Plavix® (Sanofi Aventis), is one of the salt examples used in oral dosage form. It is supplied in tablet form containing 75 mg equivalents of the clopidogrel base. Similarly to free base, clopidogrel biosulfate is also relatively unstable under increased moisture and temperature and in alkaline pHs due to its susceptibility to racemization, oxidation, and hydrolysis of a methyl ester group. Clopidogrel is a chiral molecule and can therefore exist as an R or an S enantiomer. The S-enantiomer is biologically active, while the R-enantiomer (impurity C) does not exhibit any anti-aggregation activity and is poorly tolerated. It can evoke convulsions at high doses of animals. The major circulating compound after administration is the inactive carboxylic acid derivative, which is formed by hydrolysis of the ester function by carboxylesterase. Carboxylic acid derivative (S)-(+)-(2-chlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-yl acetic acid (clopidogrel acid, Impurity A), which can be obtained by the hydrolysis of the ester group, either in vitro, catalyzed by the increased humidity, pH, and temperature, or in vivo, as a result of the action of enzyme carboxylesterase, is the main degradation product having no pharmacological activity. This implies that the content of the R-enantiomer as well as the inactive carboxylic acid derivative must be carefully controlled in clopidogrel bulk substance and drug products. The structure of those impurities listed in USP 32 and EP are shown below:

The low solubility of clopidogrel in water at neutral pH makes it very difficult to develop a bioavailable and physical stable pharmaceutical product, particularly when intravenous or oral solutions are needed. Whereas its highly pH-dependent solubility make it very challenging to make a suitable aqueous-based injectable dosage forms that will not precipitate out when contact with body fluid and will not cause injection pain, phlebitis, and even embolism upon administration. Moreover, chemical instability of clopidogrel, in the presence of moisture, heat, and alkaline pH, precludes the use of aqueous solvent in the formulation, limits its formulation to organic solvent-based liquid or freeze-dried solid, and restrict its storage condition to a low storage temperature such as refrigeration or freezing.
A number of approaches for preparing intravenous and oral liquid compositions of sparingly or poorly water-soluble basic drugs are available. These methods include micellar solubilization or drug nanoparticle suspension by means of surface-active agents; formation of complexes with cyclodextrin and its derivatives (Hydroxypropyl beta-Cyclodextrin (HPBCD) and sulfobutylether-β-cyclodextrin (SBECD)); use of various co-solvent systems; and formation of salt with strong acid with a low solution pH. However, for micellar system, surfactants have been implicated by adverse effects such as hemolysis and histamine reaction and severe anaphylaxis reaction, and for nanosuspension system wherein pure drug particles of nanosize stabilized by polymer and surfactants, potential catalytic degradation of drug substance due to higher exposure area to aqueous media and the surrounding surfactants has been reported; taste masking and injection pain is another issue for the micellar/nanosuspension system due to a higher concentration of free drug available in the aqueous medium; co-solvent systems is known for causing precipitation, injection pain and phlebitis; potential nephrotoxicity and bradycardia and reduction of blood pressure caused by cyclodextrine and its derivatives and the potential concerns of cyclodextrin binding with coadministered lipophilic drugs have been reported; and the low solution pH of weakly basic salt formed with strong acid such as clopidogrel bisulfate will cause drug-excipient and product stability issue and cause tasting issue (clopidogrel has a bittering taste), injection site irritation and pain as a result of precipitation of the drug as free base when contact with blood at neutral pH. In summary, each of these methods listed above has its inherent limitations and are insufficient to formulate clopidogrel in a biocompatible vehicle having sufficient stability, minimum side effects, and appropriate pharmadynamic profiles as a either intravenous agent or oral solution agent.
WO 2008/060934 discloses an emulsion composition containing micronized oil droplets of pure tetrahydropyridine anti platelet agent stabilized by surfactant. Even though the publication mentions that the agent could be clopidogrel, the publication only discloses emulsion compositions using clopidogrel bisulfite as the starting material. Emulsion composition using clopidogrel free base as a starting material was not disclosed in the publication, and effects of drug form (free base or salt form) on the product stability, particularly on the drug-related impurity profiles of clopidogrel was not disclosed for the composition either.
CN102697724 discloses oil in water emulsion made with clopidogrel bisulfate or amino acid salts as the starting materials. However, the publication does not disclose emulsion compositions using clopidogrel free base as the starting material and the concentration of clopidogrel free base achieved in the emulsion composition is low (≦0.15% w/v), which may require a large volume of emulsion to achieve the required dose of 300 mg, In addition effects of drug form (free base or salt form) on the product stability, particularly on the drug-related impurity profiles of clopidogrel was not disclosed for the compositions either